IGF-1 Induces GHRH Neuronal Axon Elongation during Early Postnatal Life in Mice

Nutrition during the perinatal period programs body growth. Growth hormone (GH) secretion from the pituitary regulates body growth and is controlled by Growth Hormone Releasing Hormone (GHRH) neurons located in the arcuate nucleus of the hypothalamus. We observed that dietary restriction during the early postnatal period (i.e. lactation) in mice influences postnatal growth by permanently altering the development of the somatotropic axis in the pituitary gland. This alteration may be due to a lack of GHRH signaling during this critical developmental period. Indeed, underfed pups showed decreased insulin-like growth factor I (IGF-I) plasma levels, which are associated with lower innervation of the median eminence by GHRH axons at 10 days of age relative to normally fed pups. IGF-I preferentially stimulated axon elongation of GHRH neurons in in vitro arcuate explant cultures from 7 day-old normally fed pups. This IGF-I stimulating effect was selective since other arcuate neurons visualized concomitantly by neurofilament labeling, or AgRP immunochemistry, did not significantly respond to IGF-I stimulation. Moreover, GHRH neurons in explants from age-matched underfed pups lost the capacity to respond to IGF-I stimulation. Molecular analyses indicated that nutritional restriction was associated with impaired activation of AKT. These results highlight a role for IGF-I in axon elongation that appears to be cell selective and participates in the complex cellular mechanisms that link underfeeding during the early postnatal period with programming of the growth trajectory.

围产期（perinatal period）营养可程序化调控机体生长。垂体分泌的生长激素（GH）可调控机体生长，其分泌受下丘脑弓状核（arcuate nucleus of the hypothalamus）内的生长激素释放激素（GHRH）神经元调控。本研究观察到，小鼠出生后早期（即哺乳期）的膳食限制，会通过永久性改变垂体生长轴（somatotropic axis）的发育进程，影响其产后生长。该发育改变或可归因于此关键发育阶段内生长激素释放激素信号通路的缺失。事实上，与正常喂养的幼崽相比，喂养不足的幼崽血浆胰岛素样生长因子I（IGF-I）水平显著降低，且在出生后10日龄时，其中正中隆起（median eminence）的GHRH轴突神经支配密度较正常喂养幼崽更低。在体外培养的7日龄正常喂养幼崽弓状外植体中，IGF-I可优先促进GHRH神经元的轴突延伸。该IGF-I刺激效应具有细胞选择性：同时通过神经丝标记或AgRP免疫组化可视化的其他弓状神经元，并未对IGF-I刺激产生显著响应。此外，同龄喂养不足幼崽弓状外植体中的GHRH神经元，丧失了对IGF-I刺激的响应能力。分子生物学分析显示，营养限制与AKT激活受损密切相关。上述研究结果表明，IGF-I在轴突延伸过程中发挥的作用具有细胞选择性，其参与了出生后早期喂养不足与生长轨迹程序化之间的复杂细胞调控机制。